The present invention is concerned with novel aromatic carboxylic acid derivatives of the formula: 
wherein
R1 is a group of the formula 
R2 is C2-8-alkanoyl, C2-8-alkyl, C2-8-alkenyl, C2-8-alkynyl or xe2x80x94OCH2R3;
R3 is hydrogen, C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl;
R4 to R9 each independently are hydrogen or C1-5-alkyl; or
R8 and R9 together are (CRaRb)n, Ra and Rb are hydrogen or C1-5-alkyl, n is 1, 2 or 3 and R4 to R7 are the same as above; or
R8 and R9 together are (CRaRb)n and R4 and R6 together are methylene or ethylene which are unsubstituted or substituted by hydroxy, and Ra, Rb, R5, R7 and n are the same as above;
R10 is carboxyl, C1-6-alkoxycarbonyl or mono- or di-(C1-6-alkyl)carbamoyl and the dotted bond in formula (a) is optional; and pharmaceutically acceptable salts of carboxylic acids of formula I.
The present invention is concerned with novel aromatic carboxylic acid derivatives which are useful for treating photodamaged skin. The invention comprises compounds of the formula: 
wherein
R1 is a group of the formula: 
R2 is C2-8-alkanoyl, C2-8-alkyl, C2-8-alkenyl, C2-8-alkynyl or xe2x80x94OCH2R3;
R3 is hydrogen, C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl;
R4 to R9 each independently are hydrogen or C1-5-alkyl; or
R8 and R9 together are (CRaRb)n, Ra and Rb are hydrogen or C1-5-alkyl, n is 1, 2 or 3 and R4 to R7 are the same as above; or
R8 and R9 together are (CRaRb)n and R4 and R6 together are methylene or ethylene, which can be substituted by hydroxy, and Ra, Rb, R5, R7 and n are the same as above;
R10 is carboxyl, C1-6-alkoxycarbonyl or mono- or di-(C1-6-alkyl)carbamoyl and the dotted bond in formula (a) is optional; and pharmaceutically acceptable salts of carboxylic acids of formula I.
Particularly, the invention comprises compounds of the formula: 
wherein
R2 is C2-8-alkanoyl, C2-8-alkyl, C2-8-alkenyl, C2-8-alkynyl or xe2x80x94OCH2R3;
R3 is hydrogen, C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl;
R5 and R7 each independently are hydrogen or C1-5-alkyl;
R4 and R6 each independently are hydrogen or C1-5-alkyl, or taken together are methylene or ethylene which are unsubstituted or substituted by hydroxy;
Ra and Rb each are independently hydrogen or C1-5-alkyl;
R10 is carboxyl, C1-6-alkoxycarbonyl or mono- or di-(C1-6-alkyl)carbamoyl;
and pharmaceutically acceptable salts of carboxylic acids of formula Ib. Ra and Rb are preferably hydrogen.
The invention also comprises compounds of the formula: 
wherein
R2 is C2-8-alkanoyl, C2-8-alkyl, C2-8-alkenyl, C2-8-alkynyl or xe2x80x94OCH2R3;
R3 is hydrogen, C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl;
R5 and R7 each independently are hydrogen or C1-5-alkyl;
R4 and R6 each independently are hydrogen or C1-5-alkyl, or taken together are methylene or ethylene which are unsubstituted or substituted by hydroxy;
Ra, Raxe2x80x2, Rb and Rbxe2x80x2 each are independently hydrogen or C1-5-alkyl;
R10 is carboxyl, C1-6-alkoxycarbonyl or mono- or di-(C1-6-alkyl)carbamoyl;
and pharmaceutically acceptable salts of carboxylic acids of formula Ib. Ra, Raxe2x80x2, Rb and Rbxe2x80x2 are preferably hydrogen. The invention also comprises compounds of the formula: 
wherein
R2 is C2-8-alkanoyl, C2-8-alkyl, C2-8-alkenyl, C2-8-alkynyl or xe2x80x94OCH2R3;
R3 is hydrogen, C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl;
R5 and R7 each independently are hydrogen or C1-5-alkyl;
R4 and R6 each independently are hydrogen or C1-5-alkyl, or taken together are methylene or ethylene which are unsubstituted or substituted by hydroxy;
Ra, Raxe2x80x2, Rb and Rbxe2x80x2 each are independently hydrogen or C1-5-alkyl;
R10 is carboxyl, C1-6-alkoxycarbonyl or mono- or di-(C1-6-alkyl)carbamoyl;
and pharmaceutically acceptable salts of carboxylic acids of formula Ib. Ra, Raxe2x80x2, Rb and Rbxe2x80x2 are preferably hydrogen.
The invention also comprises compounds of the formula: 
wherein
R2 is C2-8-alkanoyl, C2-8-alkyl, C2-8-alkenyl, C2-8-alkynyl or xe2x80x94OCH2R3;
R3 is hydrogen, C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl;
R5 and R7 each independently are hydrogen or C1-5-alkyl;
R4 and R6 each independently are hydrogen or C1-5-alkyl, or taken together are methylene or ethylene which are unsubstituted or substituted by hydroxy;
Ra, Raxe2x80x2, Raxe2x80x3, Rb Rbxe2x80x2 and Rbxe2x80x3 each are independently hydrogen or C1-5-alkyl;
R10 is carboxyl, C1-6-alkoxycarbonyl or mono- or di-(C1-6-alkyl)carbamoyl;
and pharmaceutically acceptable salts of carboxylic acids of formula Ic. Ra, Raxe2x80x3, Rb and Rbxe2x80x3 are preferably hydrogen. Raxe2x80x2 and Rbxe2x80x2 are preferably hydrogen or methyl.
The invention also comprises compounds of the formula: 
wherein
R2 is C2-8-alkanoyl, C2-8-alkyl, C2-8-alkenyl, C2-8-alkynyl or xe2x80x94OCH2R3;
R3 is hydrogen, C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl;
R5 and R7 each independently are hydrogen or C1-5-alkyl;
R4 and R6 each independently are hydrogen or C1-5-alkyl, or taken together are methylene or ethylene, which are unsubstituted or substituted by hydroxy;
Ra and Rb each are independently hydrogen or C1-5-alkyl;
R10 is carboxyl, C1-6-alkoxycarbonyl or mono- or di-(C1-6-alkyl)carbamoyl;
and pharmaceutically acceptable salts of carboxylic acids of formula Id. Ra and Rb are preferably hydrogen.
The invention also comprises compounds of the formula: 
wherein
R2 is C2-8-alkanoyl, C2-8-alkyl, C2-8-alkenyl, C2-8-alkynyl or xe2x80x94OCH2R3;
R3 is hydrogen, C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl;
R5 and R7 each independently are hydrogen or C1-5-alkyl;
R4 and R6 each independently are hydrogen or C1-5-alkyl, or taken together are methylene or ethylene which are unsubstituted or substituted by hydroxy;
Ra, Raxe2x80x2, Rb and Rbxe2x80x2 each are independently hydrogen or C1-5-alkyl;
R10 is carboxyl, C1-6-alkoxycarbonyl or mono- or di-(C1-6-alkyl)carbamoyl;
and pharmaceutically acceptable salts of carboxylic acids of formula Ie. Ra, Raxe2x80x2, Rb and Rbxe2x80x2 are preferably hydrogen.
The invention also comprises compounds of the formula: 
wherein
R2 is C2-8-alkanoyl, C2-8-alkyl, C2-8-alkenyl, C2-8-alkynyl or xe2x80x94OCH2R3;
R3 is hydrogen, C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl;
R5 and R7 each independently are hydrogen or C1-5-alkyl;
R4 and R6 each independently are hydrogen or C1-5-alkyl, or taken together are methylene or ethylene which are unsubstituted or substituted by hydroxy;
Ra, Raxe2x80x2, Raxe2x80x3, Rb Rbxe2x80x2 and Rbxe2x80x3 each are independently hydrogen or C1-5-alkyl;
R10 is carboxyl, C1-6-alkoxycarbonyl or mono- or di-(C1-6-alkyl)carbamoyl;
and pharmaceutically acceptable salts of carboxylic acids of formula If. Ra, Raxe2x80x3, Rb and Rbxe2x80x3 are preferably hydrogen. Raxe2x80x2 and Rbxe2x80x2 are preferably hydrogen or methyl.
In all the above embodiments of the invention, preferably R4, R5, R6, and R7 are independently hydrogen or methyl, or R5 and R7 are independently hydrogen or methyl and R4 and R6 taken together are methylene or ethylene which are unsubstituted or substituted by hydroxy. In all the above embodiments of the invention, R10 is preferably carboxyl, and R2 is is preferably n-C2-8 alkyl or xe2x80x94OCH2R3 wherein R3 is hydrogen or n-C1-6 alkyl.
The invention is furthermore concerned with pharmaceutical preparations comprising compounds of the invention or their salts and with a process for the manufacture of said compounds.
The terms xe2x80x9cC1-6xe2x80x9d, xe2x80x9cC2-6xe2x80x9d, xe2x80x9cC1-5xe2x80x9d, xe2x80x9cC1-7xe2x80x9d and xe2x80x9cC2-8xe2x80x9d used herein denote groups with 1-6, 2-6, 1-5, 1-7 and 2-8 carbon atoms. Alkyl residues R2 and R3 are preferably straight-chain alkyl residues such as ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl. Alkenyl residues R2 and R3 are preferably straight-chain alkenyl residues such as vinyl, 1- and 2-propenyl, and 2-butenyl. Alkynyl residues R2 and R3 are preferably ethynyl, 1- and 2-propynyl, 1- and 2-butynyl. C2-8-alkanoyl residues are preferably straight-chain alkanoyl residues such as acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl and octanoyl.
The compounds of the invention and their salts can be manufactured in accordance with the invention by
a) reacting a compound of the formula: 
xe2x80x83with a compound of the formula: 
wherein one of the groups A and B is xe2x80x94CH2P(O)(OAlk)2 or xe2x80x94CH2P+ (Ph)3Yxe2x88x92 and the other symbol A or B is formyl; Ph is phenyl or substituted phenyl; Alk is C1-6-alkyl; and Yxe2x88x92 is an anion and R11 is C1-6-alkoxy-carbonyl; and the remaining symbols have the significance given above; or
b) reacting a compound of the formula: 
xe2x80x83with a compound of the formula: 
wherein Hal is bromine or iodine and R11 is C1-6-alkoxy-carbonyl; and the remaining R-groups have the significance given above;
or
c) reacting a compound of the formula: 
xe2x80x83with a compound of the formula: 
wherein B is xe2x80x94CH2P(O)(OAlk)2 or xe2x80x94CH2P+(Ph)3Yxe2x88x92 and R11 is C1-6-alkoxycarbonyl,
or
d) reacting a compound of the formula: 
xe2x80x83with a compound of the formula: 
wherein Hal is bromine or iodine and the remaining R-groups have the significance given above,
or
e) oxidizing the hydroxy group in a compound of the formula: 
wherein R12 is C1-7-alkyl, to the oxo group,
and, if desired, in the resulting compound of formula I converting the alkoxycarbonyl group into a carboxyl group or a pharmaceutically acceptable salt thereof or into a mono- or di-C1-6-(alkyl)carbamoyl group.
The foregoing reactions can be carried out according to methods known per se.
The reaction of the compounds II and III in accordance with process variant a) as well as VII and VIII in accordance with process variant c) can be carried out according to the known methods of the Wittig or Horner reaction.
In the case of the Wittig reaction, i.e., when using compounds of formulae II and III with A or B=xe2x80x94CH2P+(Ph)3Yxe2x88x92, the components are reacted with one another in the presence of an acid-binding agent, e.g. in the presence of a strong base, such as e.g. butyllithium, sodium hydride or the sodium salt of dimethyl sulphoxide, or K tert.butylate, but primarily in the presence of an ethylene oxide which is optionally substituted by lower alkyl such as 1,2-butylene oxide, optionally in a solvent, e.g. in an ether, such as diethyl ether or tetrahydrofuran, or in an aromatic hydrocarbon, such as benzene, in a temperature range lying between about xe2x88x92200xc2x0 C. and the boiling point of the reaction mixture.
Of the inorganic acid anions Yxe2x88x92 the chloride and bromide ion or the hydrosulphate ion is preferred and of the organic acid anions the tosyloxy ion is preferred. The residue Ph is preferably phenyl.
In the case of the Horner reaction, i.e., when using compounds of formulae II or III with A or B=xe2x80x94CH2P(O)(OAlk)2, the components are condensed with the aid of a base and preferably in the presence of an inert organic solvent, e.g., with the aid of sodium hydride in benzene, toluene, dimethylformamide, tetrahydrofuran, dioxan or 1,2-dimethoxy ethers or also with the aid of a sodium alcoholate in an alkanol, e.g., sodium methylate in methanol, in a temperature lying between about xe2x88x9220xc2x0 C. and the boiling point of the reaction mixture.
The coupling reactions b) and d) can be catalyzed, starting directly from the acetylenes VI and, respectively, X, by phosphine complexes of palladium and nickel and Cu(I) salts. In all cases the presence of a base is convenient, for example an organic nitrogen base, such as triethylamine, piperidine or pyridine, or an alkali metal alcoholate, such as sodium methanolate or sodium phenolate. If desired, the reaction is carried out in a solvent, preferably in benzene, dimethylformamide or tetrahydrofuran. The reaction conveniently takes place at a temperature of 20 to 150xc2x0 C.
The oxidation e) can be carried out with oxidation agents such as MnO2 in an inert organic solvent, e.g., a chlorinated hydrocarbon such as methylene chloride, preferably at room temperature.
Compounds of the invention in which R1 represents a group of formula (a) in which the dotted bond is absent; or a group of formula (b); and R2 is a group as defined above except an alkanoyl residue can be obtained according to process variant a).
Compounds of the invention in which R1 represents a group (a) in which the dotted bond is present can be obtained according to process variants b), c) and d).
Compounds in which R2 represents a C2-8-alkanoyl residue are obtained according to process variant e).
The carboxylic acid ester group in a compound of the invention can be saponified to the carboxyl group and this can then be converted into a salt or an amide.
A carboxylic acid ester of the invention can be amidated directly as described hereinafter or can be hydrolyzed in a manner known per se, e.g., by treatment with alkali, especially by treatment with aqueous-alcoholic sodium or potassium hydroxide, in a temperature range lying between room temperature and the boiling point of the reaction mixture, to the carboxylic acid which can be amidated via an acid halide.
A carboxylic acid of the invention can be converted in a manner known per se, e.g., by treatment with thionyl chloride, or phosphorus trichloride in toluene or oxalyl chloride in DMF/benzene into the acid chloride which can be converted by reaction with alcohols into esters or with amines into the corresponding amide.
A carboxylic acid ester of the invention can be converted directly into the corresponding amide, e.g. by treatment with lithium amide. The lithium amide is advantageously reacted with the particular ester at room temperature.
All of these conversions can be carried out according to methods known per se.
Examples of pharmaceutically acceptable salts into which the carboxylic acids of the invention can be converted are alkali metal salts, such as Na and K salts, alkaline earth metal salts, such as Ca and Mg salts, and ammonium salts, e.g. salts with alkylamines and hydroxyalkylamines or with other organic bases, such as dimethylamine, diethanolamine and piperidine.
The compounds of the invention can occur as E/Z isomer mixtures which can be separated according to methods known per se. The E-(all-E) isomers are preferred.
The compounds of formulae II-X, insofar as they are not known or their preparation is not described hereinafter, can be prepared in analogy to known procedures or procedures described hereinafter.
The compounds in accordance with the invention act as selective ligands of retinoic acid xcex3-receptors (RAR-xcex3). They can be used for the treatment of photodamaged skin. The compounds of the invention are also useful for the prophylaxis of photo- and age-damaged skin and for treating age-damaged skin as well as for the promotion of wound healing, for example of incised wounds, such as surgical wounds, wounds caused by burns and other wounds caused by cutaneous trauma. The utility of the compounds in accordance with the invention for this purpose can be determined by any conventional means. Preferably, the determination is made using the models described in Science, 237: 1333-1336 (1987) and J. Pathol., 129: 601-613 (1987). The utility of the compounds of the invention to repair photo-damaged skin is preferably determined through the hairless mouse procedure described below.
Furthermore, the compounds in accordance with the invention can be used for the therapy and prophylaxis of dermatological disorders which are accompanied by epithelial lesions, e.g., acne and psoriasis, as well as malignant and premalignant epithelial lesions, tumours and precancerous changes to the mucous membrane in the mouth, tongue, larynx, oesophagus, bladder, cervix and colon.
The compounds of the invention and their salts can accordingly be used in the form of pharmaceutical preparations.
The preparations for systemic use can be produced, e.g., by adding a compound of the invention or a salt thereof as the active ingredient to non-toxic inert solid or liquid carriers which are usual in such preparations.
The preparations can be administered enterally, parenterally or topically. Preparations in the form of tablets, capsules, dragees, syrups, suspensions, solutions and suppositories are, e.g., suitable for enteral administration. Preparations in the form of infusion or injections solutions are suitable for parental administration.
For enteral and parental administration the compounds of formula I can be administered to adults in amounts of about 1-100 mg, preferably 5-30 mg/day.
For topical use the active ingredients are conveniently used in the form of ointments, tinctures, creams, solutions, lotions, sprays, suspensions and the like. Ointments and creams as well as solutions are preferred. These preparations designed for topical use can be produced by mixing the active ingredients with non-toxic, inert solid or liquid carriers which are suitable for topical treatment and which are usual in such preparations.
For topical use there are conveniently suitable about 0.1-5%, preferably 0.3-2%, solutions as well as about 0.1-5%, preferably 0.3-2%, salves or creams.
If desired, an antioxidant, e.g., tocopherol, N-methyl-g-tocopheramine as well as butylated hydroxyanisole or butylated hydroxytoluene, can be admixed with the preparations.
The efficacy of the compounds in accordance with the invention in the treatment of photo-damaged skin will be evident from the experimental procedures described hereinafter:
Hairless mice (HRS/J strain, Jackson Labs, aged 5-7 weeks at the beginning of the experiment) were irradiated three times a week with an arrangement of 8 Westinghouse irradiation lamps (FS40) which were placed about 20 cm above the animals. The radiation dose was controlled by a commercial phototherapeutic control device. The UV-B dose was chosen such that the dosage scarcely exceeded 0.06 J/cm2, caused a minimal erythema, but no burning or scarring. After a total dose of about 3.5 J/cm2 there resulted a significant elastosis which was evident from a histological report and which was confirmed by measuring the elastin using a radioimmunoassay for desmosin in the total skin. The desmosin content increased by two- to three-fold after 3.5 J/cm2 UV-B irradiation. In order to make good the skin damage, the UV irradiation was interrupted and groups of animals were treated three times a week with different doses of compounds of formula I dissolved in acetone. These solutions were prepared freshly each week such that the dosage to be administered was present in 100 ml of acetone and were applied topically to an area of about 10 cm2 on the backs of the animals. A controlled group was treated only with acetone.
After treatment for 10 weeks the animals were killed, skin preparations were prepared and the extent of the recovery was measured quantitatively by Luna staining of the elastin. In this experimental model the skin recovery is defined as the appearance of a normal dermis which extends from the epidermis to the layer of compressed elastin. The extent of the recovery was given by the width of this zone. The area of the zone on a standard length of the histological section was measured and the result was expressed as the total surface in mm2 per 20 microscopic field. The results are compiled in Table I.